Related Experiment Video

Updated: Apr 2, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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The Moving Target: Cis-Mutation-Driven Resistance to p53-Y220C Reactivator

Yanqing Liu1, Wei Gu1,2

  • 1Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Cancer Discovery
|April 1, 2026
PubMed

Insights

Rezatapopt resistance in the PYNNACLE trial arose from new TP53 mutations. These secondary mutations in the Y220C-mutant background reduced the drug

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The p53 protein is a critical tumor suppressor. Mutations in TP53, including Y220C, are common in various cancers.
  • Rezatapopt is a novel therapeutic agent designed to reactivate p53 with the Y220C mutation.

Purpose of the Study:

  • To investigate the mechanisms of resistance to rezatapopt observed in the PYNNACLE clinical trial.
  • To identify genetic alterations that confer resistance to p53-Y220C reactivation therapy.

Main Methods:

  • Genomic analysis of patient samples from the PYNNACLE trial.
  • Sequencing of the TP53 gene in tumors exhibiting rezatapopt resistance.

Main Results:

  • Rezatapopt treatment selected for secondary mutations within the TP53 gene in patients with the Y220C mutation.
  • These acquired TP53 mutations abrogated the therapeutic efficacy of rezatapopt, leading to treatment resistance.

Conclusions:

  • Secondary TP53 mutations are a key mechanism of acquired resistance to rezatapopt.
  • Understanding these resistance mechanisms is crucial for developing future strategies for p53-targeted therapies.

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